Neuroscience Training Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA.
Clin Cancer Res. 2012 Jul 1;18(13):3628-36. doi: 10.1158/1078-0432.CCR-12-0339. Epub 2012 May 15.
Glioblastoma multiforme (GBM) is a poorly treated human brain cancer with few established clinically useful molecular prognostic markers. We characterized glioblastoma stem-like cells (GSC) according to developmental neural lineage markers and correlated their expression with patient survival.
Immunoblot array of neural lineage markers classified five independently isolated human GSC lines into three classes exhibiting differential expression of oligodendrocyte progenitor cells (OPC), astrocyte progenitor cells (APC), and neural progenitor cells (NPC) markers. Immunodeficient mice were orthotopically implanted with each cell line to evaluate tumor infiltration and recipient survival. 2',3'-Cyclic-nucleotide 3'-phosphodiesterase (CNP) antigenic expression was used to evaluate a clinically annotated GBM tissue microarray with 115 specimens.
We report that molecular classification of patient-derived GSCs using neural lineage markers show association with differential xenograft invasiveness, and also show significant correlation to survival in both the mouse model and human patients. Orthotopic implantation into immunodeficient mice showed Ki-67 proliferative index independent xenograft infiltration: class I GSCs (OPC and NPC positive) established focal lesions, class II GSCs (NPC positive) formed minimally invasive lesions, and class III GSCs (APC positive) established highly infiltrative lesions. The OPC marker, CNP also exhibited high expression in focal xenografts versus low expression in invasive xenografts. Differential CNP expression correlated with mouse model survival, and CNP immunoassay of a large GBM tissue microarray also showed significant differential patient survival.
GSC classification with developmental neural lineage markers revealed CNP as a novel and potentially useful clinical prognosis marker, and suggests clinical importance for patient-specific GSC analysis.
多形性胶质母细胞瘤（GBM）是一种治疗效果差的人类脑癌，目前很少有明确的临床有用的分子预后标志物。我们根据发育性神经谱系标志物对胶质母细胞瘤干细胞（GSC）进行了特征描述，并将其表达与患者的生存情况进行了关联。
神经谱系标志物的免疫印迹分析将五个独立分离的人 GSC 系分为三类，它们表现出少突胶质前体细胞（OPC）、星形胶质前体细胞（APC）和神经前体细胞（NPC）标志物的差异表达。将每种细胞系原位植入免疫缺陷小鼠中，以评估肿瘤浸润和受体的存活情况。使用 2'，3'-环核苷酸 3'-磷酸二酯酶（CNP）抗原表达来评估具有 115 个标本的临床注释 GBM 组织微阵列。
我们报告说，使用神经谱系标志物对患者来源的 GSCs 进行分子分类与异种移植物侵袭的差异相关，并且在小鼠模型和人类患者中均与存活情况显著相关。免疫缺陷小鼠的原位植入显示 Ki-67 增殖指数独立的异种移植物浸润：I 类 GSCs（OPC 和 NPC 阳性）建立了局灶性病变，II 类 GSCs（NPC 阳性）形成了最小侵袭性病变，III 类 GSCs（APC 阳性）建立了高度侵袭性病变。OPC 标志物 CNP 也在局灶性异种移植物中高表达，而在侵袭性异种移植物中低表达。差异 CNP 表达与小鼠模型的存活相关，并且 CNP 免疫测定法对大型 GBM 组织微阵列也显示出显著的患者生存差异。
用发育性神经谱系标志物对 GSC 进行分类，揭示了 CNP 作为一种新的、潜在有用的临床预后标志物的重要性，并提示了对患者特异性 GSC 分析的临床重要性。
